There is an increasing incidence of life-threatening systemic fungal infections due to Candida species. Although fluconazole is currently the most widely used drug for preventing and treating these infections, its effectiveness is compromised, not only by the fact that it is fungistatic, but also by the recent emergence of fluconazole-resistant Candida strains. The therapeutic options for treating fluconazole-resistant Candida infections are limited to drugs with severe toxicity. In this project we plan to test the feasibility of developing an improved antifungal agent by potentiating the activity of fluconazole. A chemical library will be screened, first, for compounds which exhibit fungicidal activity in combination with fluconazole and, second, for compounds potentiating fluconazole activity in strains exhibiting intrinsic or acquired fluconazole resistance mechanisms. Preliminary screening of a portion of this library has already identified a promising candidate potentiator. The potentiating effects of the identified compounds will be quantitated and characterized and preliminary toxicity testing and structure activity analysis will be performed.The combination of fluconazole with a potentiator of its activity could form a powerful combination antifungal agent and extend the therapeutic options currently available for treating Candida infections. PROPOSED COMMERCIAL APPLICATIONS: The envisioned commercial product is a combination of fluconazole with a drug which potentiates its antifungal activity. Such a combination drug would have a major impact on the therapeutic and prophylactic treatment options for systemic Candida infections.